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4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells
- Source :
- Frontiers in Immunology, Vol 11 (2020)
- Publication Year :
- 2020
- Publisher :
- Frontiers Media S.A., 2020.
-
Abstract
- While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-κB pathway activation. Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.
Details
- Language :
- English
- ISSN :
- 16643224
- Volume :
- 11
- Database :
- Directory of Open Access Journals
- Journal :
- Frontiers in Immunology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.b9d350a6df9418a9d77903e60fcba47
- Document Type :
- article
- Full Text :
- https://doi.org/10.3389/fimmu.2020.539654